Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma, lung cancer), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7), cyclin-dependent kinase 12 (CDK12), or cyclin-dependent kinase 13 (CDK13)), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

What is claimed is: 
     
       1. A compound having Formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 Ring A is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
          wherein Ring A may be substituted with a substituent selected from the group consisting of halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14  aryl, and optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl; 
         W B  is CR B2 , wherein R B2  is selected from the group consisting of halogen, substituted or unsubstituted C 3 -C 10  carbocyclyl, unsubstituted C 1-6  alkyl, C 1-6  alkyl substituted with one or more halogen, and —CN; 
         R B1  is hydrogen or halogen; 
         L 1  is —N(R L1 )—, wherein each instance of R L1  is independently hydrogen or unsubstituted C 1-6  alkyl; 
         each instance of R c  is independently selected from the group consisting of halogen, —OR C1 , and substituted or unsubstituted C 1-6  alkyl, wherein each instance of R C1  is independently hydrogen or substituted or unsubstituted C 1-6  alkyl, or two R c  are taken together to form an optionally substituted 3- to 10-membered heterocyclyl or C 3 -C 8  carbocyclyl fused to the ring to which the R C  are bound; 
         L 2  is selected from the group consisting of —N(R L2 )C(═O)—, —C(═O)N(R L2 )—, —N(R L2 )—(C 1-2  alkylene)-, —N(R L2 )—, —NH—S(O) 2 —, and —S(O) 2 —NH—, wherein each instance of R L2  is independently hydrogen, or substituted or unsubstituted C 1-6  alkyl; 
         each instance of R D  is independently halogen or optionally substituted C 1 -C 4  alkyl; 
         R E  is selected from: 
       
       
         
           
           
               
               
           
         
         R E1  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14  aryl, optionally substituted 3- to 10-membered heteroaryl, —CN, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 ,—Si(R E1a ) 3 , and —SR E1a , wherein each occurrence of R E1a  is independently selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 ,C 10 , or C 14  aryl, and optionally substituted 3- to 10-membered heteroaryl, or two R E1a  groups are joined to form an optionally substituted 3- to 10-membered heterocyclic ring; 
         R E2  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 ,C 10 , or C 14  aryl, optionally substituted 3- to 10-membered heteroaryl, —CN, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N( E2a ) 2  and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14  aryl, and optionally substituted 3- to 10-membered heteroaryl, or two R E2a  groups are joined to form an optionally substituted 3- to 10-membered heterocyclic ring; 
         R E3  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14  aryl, optionally substituted 3- to 10-membered heteroaryl, —CN, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a  is independently selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -C 10  carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14  aryl, optionally substituted 3- to 10-membered heteroaryl, or two R E3a  groups are joined to form an optionally substituted 3- to 10-membered heterocyclic ring; 
         optionally R E1  and R E3 , or R E2  and R E3 , or R El  and R E2  are joined to form an optionally substituted C 3 -C 10  carbocyclic or optionally substituted 3- to 10-membered heterocyclic ring; 
         n is 0, 1, or 2; and 
         p is 0 or 1. 
       
     
     
       2. The compound of  claim 1 , wherein R B2  is chloro, cyclopropyl, or —CN. 
     
     
       3. The compound of  claim 1 , wherein L 1  is —NH—. 
     
     
       4. The compound of  claim 1 , wherein each instance of R c  is independently fluoro, —OH, or methyl, or Ring C and all instances of R c  are taken together to form a ring: 
       
         
           
           
               
               
           
         
       
       wherein “2” represents a portion of the ring bound to L 1 , and “3” represents a portion of the ring bound to L 2 . 
     
     
       5. The compound of  claim 1 , wherein n is 1. 
     
     
       6. The compound of  claim 1 , wherein L 2  is —NHC(═O)—, —C(═O)NH—, —NH—(C 1-2  alkylene)—, or —NH—. 
     
     
       7. The compound of  claim 1 , wherein p is 0. 
     
     
       8. The compound of  claim 1 , wherein R E  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       9. The compound of  claim 1 , selected from any one of Compounds 100-106, 108, 109, 112-126, 128-132, 135-142, 146, 147, 150-154, 156-162, 164, and 173-178. 
     
     
       10. A pharmaceutical composition comprising a compound of claim l, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
       11. The compound of  claim 1 , wherein ring A is 
       
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 1 , wherein ring C is 
       
         
           
           
               
               
           
         
       
       wherein “2” represents a portion of ring C bound to L 1 , and “3” represents a portion of ring C bound to L 2 . 
     
     
       13. The compound of  claim 1 , wherein L 2  is *—NH—C(O)—, “*” represents a point of attachment to ring C, and L 1  and L 2  are meta to one another. 
     
     
       14. The compound of  claim 1 , wherein R E  is 
       
         
           
           
               
               
           
         
       
     
     
       15. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       16. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       17. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       18. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       19. The compound of  claim 1 , wherein the compound is